[A Pediatric Case of Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion(MERS)with Recurrent TIA-like Symptoms over a Prolonged Period].

We report a rare case of pediatric clinically mild encephalitis/encephalopathy with a reversible splenial lesion(MERS)associated with transient ischemic attack(TIA)-like symptoms. A 13-year-old boy who presented with transient left hemiparesis and dysarthria was transferred to our hospital. He had experienced similar symptoms at the age of nine years and was diagnosed with MERS type 2 due to the typical clinical course and MR imaging findings. His elder brother showed a similar clinical history at the age of eight years. DW-MR images on admission revealed high signal intensity areas in the splenium of the corpus callosum and deep white matter. The territories were depicted as low intensity on apparent diffusion coefficient maps and slightly high intensity on T2-weighted images. Recurrence of MERS type 2 was considered because the symptoms of the patient disappeared within several hours and the abnormal signal intensities markedly decreased on the follow-up DWI performed eight days after initial MR imaging. The abnormal MR imaging findings completely disappeared after five weeks. After discharge, the patient experienced eight TIA-like episodes with a similar clinical course and MR imaging findings over a period of six years. MERS associated with TIA-like episodes is extremely rare, especially MERS associated with recurrent episodes in multiple phases over a long period, as seen in the present case. In addition, the findings in the last two MR imaging scans involving the internal capsule, thalamus, and midbrain were highly unusual and maybe considered to be indicative of an advanced form of MERS type 2, as reported in other familial cases.

[Task-shifting Carried out by an Emergency Department's Stroke Hotline and Medical Care Support Conducted by Nurse Practitioners].

Our hospital serves as the main hub for eight remote island hospitals(RIHs)in Nagasaki Prefecture, Japan. The shortage of stroke physicians, which has led to overwork, is a major concern. Several "task-shifting" systems were adopted to avoid physician burnout. First, the emergency department established a hotline system for receiving emergency calls regarding a stroke, and which managed initial care until the stroke physicians arrived(called the Nagasaki Medical Center stroke hotline system: N-SHOT)in 2014. The rt-PA administration rate increased from 3.3% in the Pre-N-SHOT group to 6.7% in the N-SHOT group. Second, the 'isolated islands stroke hotline system(I-SHOT)', with which physicians in RIHs participate in cooperation with N-SHOT, was started in 2017. After I-SHOT was introduced, the number of patients treated with the drip and ship method using teleradiology and 24-h helicopter transportation increased from 20(2010-2016)to 29 cases in 2017-2018. Additionally, new information and communication technology(ICT)using smart devices was introduced into the teleradiology system for task support. Third, on behalf of stroke physicians, nurse practitioners(NP)helped bedridden patients who had been delivered from RIHs and who had received acute treatment, and returned to their islands by helicopter or airplane as transitions of care. N-SHOT is smoothly operated by each hospital department without reducing the quality of the stroke hotline. It has contributed to an increase in rt-PA and mechanical thrombectomy cases; I-SHOT has had the same effect. Task-shifting and task support with N- & I-SHOT, the smooth transfer system by NP, and the new ICT are considered to be useful for reducing the overall burden of stroke physicians.

[Durable remission attained with plasmapheresis and intravenous immunoglobulin therapy in a patient with acute exacerbation of GVHD-related myasthenia gravis].

A 17-year-old male underwent a second bone marrow transplantation using a 6/8 allele HLA-matched unrelated donor. On day 100 after transplantation, steroid treatment for chronic graft-versus-host disease (GVHD) was started. On day 766, the patient experienced general fatigue, followed by double vision, ptosis, and dysphagia on day 810. Based on the positivity of the acetylcholine receptor antibody and a waning electromyography pattern, he was diagnosed with GVHD-related myasthenia gravis (MG). On day 861, we initiated plasmapheresis (PE), followed by the administration of intravenous immunoglobulin (IVIg) ; this treatment attenuated the bulbar symptoms of MG. Although the steroid treatment was continued, we restarted the administration of tacrolimus. On day 2,739 after transplantation, we stopped the steroid treatment, and the patient remained in remission for MG following the cessation of the steroid treatment on day 2,897. This case suggests that PE followed by IVIg could be an effective therapeutic alternative for MG associated with GVHD.

[Internal carotid artery stenosis with repeated ischemic stroke recurrence due to mechanical stimulation by the hyoid bone and thyroid cartilage: a case report].

We present a case of internal carotid artery (ICA) stenosis caused by mechanical stimulation by the hyoid bone (HB) and thyroid cartilage (TC). A 78-year-old man with a history of right ICA stenting four years previously was admitted for abrupt onset of dysarthria and left hemiparesis and diagnosed with ischemic stroke by magnetic resonance imaging. Three-dimensional computed tomographic angiography revealed internal carotid in-stent restenosis. Furthermore, the HB and TC contacted with the right ICA. Treatment involved antiplatelet therapy, partial HB and TC resection, and carotid artery restenting. Posttreatmently, the ICA was restored and stenosis improved. Since restenosis may occur posttreatmently in patients with carotid artery stenosis caused by mechanical stimulation of the HB and TC, it is necessary to consider treatments including not only carotid artery stenting but also partial bone structures resection and carotid endarterectomy.

Fulminant Guillain-Barré syndrome secondary to Campylobacter coli infection: An autopsy case report.

The most common infection preceding Guillain-Barré syndrome (GBS) is Campylobacter jejuni enteritis, although a few patients present with Campylobacter coli. We report a case of C. coli-induced fulminant GBS. A 61-year-old woman presented with bilateral limb weakness. Nerve conduction studies revealed a reduction of amplitude and C. coli was isolated from a fecal specimen, leading to the diagnosis of GBS. Although the patient was immediately administered immunoglobulin, her symptoms rapidly worsened and she died. Peripheral nerve autopsy revealed myelin ovoid, and infiltration of CD68-positive macrophages into nerves. More effective treatments for fulminant GBS need to be developed.

[Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) with a family history: an adult case].

We present an adult case of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). A 26-year-old man with a family history of MERS presented to our hospital owing to dysarthria and dysesthesia of the right side of his body. The duration of these symptoms was approximately 4 hours. T2 and diffusion weighted MRI showed high signal intensity lesions in the bilateral deep white matter. On a 3-week follow-up MRI, the lesions had completely disappeared. We attributed this clinical course and image findings to MERS. The patient had experienced similar symptoms at the age of 8 years old. Furthermore, his younger brother showed a similar clinical history and experienced a few recurrence events during the age of 9-16 years old. The mechanism of MERS remains controversial. However, similar to our case, there are some case reports with a family history. In addition, a previous report has confirmed the existence of a heterozygous variant in the myelin regulatory factor gene in patients with MERS. Some genetic factors may induce MERS, especially with extensive white matter lesions.

Endovascular Coil Embolization for Recurrent Bow Hunter's Stroke.

Bow hunter's stroke is a rare cause of vertebrobasilar infarction. There is no consensus regarding the optimal treatment. We herein report a case of bow hunter's stroke successfully treated by endovascular treatment. A 70-year-old man presented with central vertigo. Magnetic resonance imaging (MRI) showed posterior circulation infarcts. Dynamic angiography revealed thrombus formation and hypoperfusion of the right vertebral artery upon head rotation to the left. Endovascular parent artery occlusion of the right vertebral artery was performed, and there was no recurrence at follow-up MRI. Endovascular parent artery occlusion might be a useful treatment for bow hunter's stroke.

[Paraneoplastic Cerebellar Degeneration with Lambert-Eaton Myasthenic Syndrome: A Report of an Effectively Treated Case and Systematic Review of Japanese Cases].

A 63-year-old female who developed dizziness, diplopia and subsequent gait disturbance from September X-1 year was analyzed. The first neurological findings in May X year revealed cerebellar ataxia, weakness in the proximal limbs, decreased tendon reflexes, and autonomic symptoms (ADL:mRS 3). Furthermore, an incremental phenomenon was observed in the repetitive nerve stimulation test, and she was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) based on the serum P/Q-type calcium channel (VGCC) antibody positivity. In addition, small cell lung cancer was detected by chest CT and bronchoscopy, and her cerebellar ataxia was diagnosed as paraneoplastic cerebellar degeneration (PCD). Therefore, the patient underwent chemotherapy and radiotherapy from June in X year. Six months after initiation of treatment, her cerebellar ataxia had almost disappeared and she could walk without assistance (ADL:mRS 1). The P/Q-type VGCC antibodies were also negative at that time. Cases wherein cerebellar ataxia resolved almost completely in parallel with disappearance of the serum P/Q-type VGCC antibodies are of great interest. We conducted a systematic literature review of PCD-LEMS cases in Japan reported since P/Q-type calcium channel antibody measurement was reported in 1995. As a result, 13 cases (including our study) that concurrently displayed cerebellar ataxia and LEMS were selected. The average age of the 13 patients (10 males and 3 females) was 61.5 years. Small cell carcinoma was complicated in 11 patients (10 in the lung and 1 in the oropharynx); in the other 2 patients, cancer was not found at the time of reporting (the observation period was as short as 1-2 months). The time from onset to treatment ranged between 1 week and 10 months. While 1 of the 13 patients developed cerebellar ataxia during the subsequent course of the treatment, the remaining 12 had already developed cerebellar ataxia and LEMS symptoms, although their main neurologic finding was cerebellar ataxia and they were subsequently diagnosed with LEMS after electrophysiological testing and autoantibody detection. Small cell carcinoma was found in 11 patients. We define the pathology following such a certain clinical course as PCD-LEMS. The P/Q-type VGCC antibodies were positive in 11 of the 13 cases, although their antibody titers were not necessarily very high. Treatment for the associated small cell carcinoma might have improved the neurological findings in 9 of the 11 PCD-LEMS patients. The P/Q-type VGCC antibodies were measured before and after the treatment. The PCD-LEMS symptoms improved in all patients and their antibody titers decreased. These findings indicate that P/Q-type VGCC antibodies are involved in the pathology of PCD-LEMS. Appropriate and timely treatment, at least in PCD-LEMS patients in Japan, that actively treats any associated cancer can be expected to improve not only life prognosis but also cerebellar ataxia. (Received October 15, 2018; Accepted November 5, 2018; Published January 1, 2019).

Efficacy of the Drip and Ship Method in 24-h Helicopter Transportation and Teleradiology for Isolated Islands.

Our hospital, located on the mainland, serves as a hub center for nine hospitals on the remote islands of Nagasaki Prefecture, Japan. There are no stroke specialists on these islands. We can transfer emergency patients from these islands to our hospital at any time, using a teleradiology system and three types of helicopter transport. We examined the efficacy of the drip and ship (DS) method for treating patients with acute ischemic stroke (AIS) on these islands, in comparison with patients on the mainland. From 2010 to 2017, we reviewed 98 consecutive patients with AIS who received intravenous recombinant tissue plasminogen activator (IV rt-PA) in our hospital or were transported to our hospital after IV rt-PA. Patients were divided into the Islands group (received IV rt-PA on the islands, DS; 31 cases) and the Mainland group (67 cases). The median transport distance from the islands was 112 km. The rate of patients achieving favorable outcomes was 54.8% in the Islands group and 64.2% in the Mainland group, with no significant differences. Multivariate analysis revealed that patients living on isolated islands did not have increased risks of unfavorable outcomes. Endovascular therapy (EVT), as part of the drip, ship, and retrieve method, was performed in 22.6% of patients in the Islands group and EVT in 38.8% of those in the Mainland group. The DS method seems feasible and safe for patients living on isolated islands with the use of 24-h helicopter transportation and teleradiology.

[A Case of Neuromyelitis Optica Spectrum Disease with Hypoglycorrhachia].

A 75-year-old Japanese woman developed myelitis 3years prior to her admission. She was diagnosed with HTLV-1-related myelitis and had taken prednisolone. Her myelitis relapsed several times, and serum aquaporin-4 was positive in an ELISA. She developed a sudden headache, consciousness disturbance, dysarthria, and left limb paralysis, and was admitted to our hospital. The CSF analysis revealed pleocytosis dominated by morphonuclear cells and hypoglycorrhachia. Magnetic resonance imaging revealed abnormalities in the corpus callosum, bilateral thalamus, and corticospinal tracts. We initially suspected a relapse of neuromyelitis optica spectrum disorder (NMOSD) and infection. We treated the patient with methylprednisolone pulse and antibacterial and antiviral treatment, which were not effective. Plasmapheresis was performed five times, and she gradually improved. Immunosuppressive treatment was added. It is rare for NMOSD to cause hypoglycorrhachia. This case suggests that infection may trigger an autoimmune response in NMOSD. (Received February 13, 2018; Accepted July 12, 2018; Published October 1, 2018).

GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Altered expression profiles of clock genes hPer1 and hPer2 in peripheral blood mononuclear cells of cancer patients undergoing surgery.

Patients undergoing surgery often develop symptoms of circadian rhythm disorders such as insomnia or delirium. However, the effect of surgery on the biological clock remains unknown. The present study examines the expression of clock genes in peripheral blood mononuclear cells (PBMCs) and measures plasma hormone concentrations in patients with esophageal cancer and early gastric cancer who underwent surgery. Six blood samples per day were collected from 9 patients with esophageal cancer before and after esophagectomy and from 9 patients with early gastric cancer before and after laparoscopy-assisted distal gastrectomy (LADG). The expression profiles of hPer1 and hPer2 mRNAs in PBMCs were determined by real-time RT-PCR. Plasma melatonin and cortisol concentrations were measured by radioimmunoassay. Plasma melatonin levels decreased in both groups throughout the day and plasma cortisol levels changed after surgery. The acrophase of clock gene expression was altered after surgery as follows: hPer1, from 6:19+/-1:50 to 13:59+/-0:59 (p=0.0003) and from 7:47+/-1:27 to 12:33+/-1:30 (p=0.0043) and hPer2, from 5:01+/-2:59 to 19:30+/-2:15 (p<0.0001) and from 6:49+/-1:59 to 13:39+/-3:06 (p=0.0171) in patients with esophageal and early gastric cancer, respectively. The post-operative phase change of hPer2 was more prominent after esophagectomy than after LADG. Our results suggest that surgical stress affects the peripheral clock as well as endogenous hormones in humans.

Per2 gene expressions in the suprachiasmatic nucleus and liver differentially respond to nutrition factors in rats.

BACKGROUND: We previously reported that parenteral nutrition (PN) altered the circadian rhythm of clock gene expression in the suprachiasmatic nucleus (SCN) and liver of rats. The present study was designed to investigate what factor(s) in the PN solution causes the alteration. METHODS: Male Wistar rats, kept under light and dark conditions, were divided into 4 groups after cannulation. The sham operation group received saline solution from 8 am to 8 pm at the rate of 36 mL/kg/12 hours. The glucose, amino acid, and saline groups received a glucose solution (20% wt/vol glucose, 261 kcal/kg/d, Na(+) 50 meq/L and Cl(-) 50 meq/L), an amino acid solution (4.3% wt/vol 1.78 gN/kg/d, Na +50 meq/L and Cl(-) 50 meq/L) and a saline solution from 8 am to 8 pm at a rate of 240 mL/kg/12 hours, respectively. Rats were killed every 4 hours (9 am = Zeitgeber Time (ZT) 02, 1 pm = ZT06, 5 pm = ZT10, 9 pm = ZT14, 1 am = ZT18, 5 am = ZT22, n = 3 at each point), and brain and liver samples were removed. rPer2 expression in the SCN and liver was analyzed by in situ hybridization and Northern blotting, respectively. RESULTS: Compared with the sham-operation rats, the peak time of rPer2 expression in the SCN was significantly affected by glucose, amino acid, and saline solutions. Among them, glucose-group rats showed the rPer2 expression most similar to that of diurnal PN. On the other hand, the rPer2 expression in the liver was shifted in the glucose and amino-acid-solution groups. The pattern of rPer2 expressions in the amino acid group was most similar to that of the diurnal PN group. CONCLUSIONS: These results indicate that the most potent entrainer for the SCN clock is glucose, whereas that for the liver is amino acid.

Total parenteral nutrition entrains the central and peripheral circadian clocks.

The administration schedule of total parenteral nutrition (TPN) ignores the human physiological food-intake rhythm. This study examined the effects of TPN on the central and peripheral circadian clocks. Male Wistar rats were divided into a control group, a nocturnal-TPN group, and a diurnal-TPN group. On the seventh day after TPN administration, expression of rat period2 (rPer2) and D-site binding protein (rDBP) mRNA were measured in the suprachiasmatic nucleus (SCN) and liver. While rPer2 and rDBP mRNA expression of the nocturnal-TPN rats showed similar oscillation patterns to those in the free-fed control rats both in the SCN and liver, they were shifted significantly in the diurnal-TPN rats. This phase shift occurred as early as day 1. TPN, which ignores physiological food-intake rhythms, alters the rhythm of the central and peripheral clocks.

The phenomenon of changing coiling-chirality in carbon nanocoils obtained by catalytic pyrolysis of acetylene with various catalysts.

Carbon nanocoils were prepared by the chemical vapor deposition process of the catalytic pyrolysis of acetylene at 700-800 degrees C with various catalysts. Twisting or coiling-formed carbon nanocoils with changing coiling-chirality and zigzag-formed carbon nanofibers were obtained with SUS 304, WS2, Pt-Pd, TiN, and Ni as the catalysts. Their morphologies and microstructures were examined in detail, and then the changing mechanism of the coiling-chirality was discussed. No apparent difference in the microstructure between the part of a nanocoil with changing coiling-chirality and the part of a zigzag nanofiber with changing zigzag-chirality, or between a bulk right-clockwise coil and a bulk left-clockwise coil was observed. It was supposed that changing coiling-chirality was mainly caused by the gradual or successive change in chemical composition on the thin layers present on the surface of catalyst grains during the chemical vapor deposition process.

[Successful treatment in a patient with a focal form of stiff-person syndrome using plasma exchange and intravenous immunoglobulin therapy].

We report a 42-year-old female with continuous muscle stiffness and painful muscle spasms of the right leg. The symptoms developed suddenly and worsened over the week after onset. At hospitalization, the right leg had a fixed posture of extension and the foot was plantar-flexed and internally rotated. Neurological examination revealed hyperreflexia of the right knee with positive Chaddock's sign, and stiffness and painful spasms located in the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. She could not walk due to her stiffness. There were no signs of rigidity in the left leg, upper extremities, or truncal muscles. Electrophysiological examinations revealed continuous muscle discharge. High titers of anti-glutamic decarboxylase (GAD) antibodies were detected in serum (140,000 U/ml) and cerebrospinal fluid (1,347 U/ml), confirming that the patient suffered from stiff-leg syndrome. Systemic evaluation revealed no malignant neoplasm, but revealed euthyroid Hashimoto's disease. Stiff-leg syndrome in this case was unresponsive to pharmacotherapy with diazepam and was unchanged for the first month of hospitalization. Plasma exchange therapy alleviated the clinical symptoms and decreased the anti-GAD antibody titer. After IVIg therapy, the symptoms and signs have dramatically disappeared to date but the titer of anti-GAD antibodies in serum recurred after an initial fall. To our knowledge, this is the first case of stiff-leg syndrome in Japan.

[Elevation of serum creatine kinase and low serum aldolase in the patients with KANEMI YUSHOU].

We studied the rates of the patient with the elevation of serum creatine kinase using the routine medical checkup data from KANEMI YUSHOU patients between 1995 and 2001. We also studied the serum aldolase level and light microscopic observation of muscle tissue in rats during strenuous exercise given the polychlolinated biphenyls. Fifteen percent of the patients showed the elevation of serum creatine kinase. The patients with the elevation of serum creatine kinase also showed a higher concentration of polychlolinated biphenyls in their blood. 47.7% of the patients show low aldolase. There is no interrelation between the aldolase levels and PCBs or PCQs. There is also no interrelation between the serum levels of aldolase and creatine kinase. The rats given polycholorinated biphenyls showed a slight increase of necrotic fibers during strenuous exercise. Polycholorinated biphenyls may play some role for muscle necrosis. We could not clarify the significance of low serum aldolase in KANEMI YUSHOU.

Verification of a specific reaction between an airborne antigen and an immobilized antibody at a gas-solid interface.

With a specific and strong molecular-recognition capability cultivated in humoral acquired immunity, an antibody has been extensively utilized in various applications, such as diagnostics and therapy. However, so far most of its uses have been limited to be in the liquid phase. In view of its potential uses, such as a gas-phase biosensor or a high-performance air filter, we have tried to verify a previously undescribed binding reaction between protein antigens and corresponding antibodies immobilized on a solid surface by using fluorescence resonance energy transfer between the two. Our data showed that the antibody on a solid surface specifically reacted with a protein antigen supplied from the gas phase under the normal ambient condition. Also discovered was that the reaction occurred even faster than that in the liquid phase under several assay conditions.

Injection of LPS causes transient suppression of biological clock genes in rats.

BACKGROUND: The biological clock regulates circadian rhythm and is important for sustaining homeostasis. Here we examined the response of biological clock genes to systemic inflammatory stimulation. MATERIALS AND METHODS: At 08:00 h (= Zeitgeber time [ZT] 01), male Wistar rats (7-wk-old) maintained on a 12:12 h light:dark cycle (light on 07:00-19:00 h) received intravenous injection of 1 mg/kg lipopolysaccharide (LPS group) or 0.3 mL saline (control group). They were then sacrificed every 4 h (09:00 h = ZT 02, 13:00 h = ZT 06, 17:00 h = ZT 10, 21:00 h = ZT 14, 01:00 h = ZT 18, 05:00 h = ZT 22) over a 2-d period, and blood, brain, and liver samples were obtained for analysis (n = 4 at each time for each group). The expression levels of clock gene, rPer2, and those of clock controlled gene, rDBP, were quantified in the suprachiasmatic nucleus by in situ hybridization, while those of rPer1, rPer2, rDBP, rPPARA, and rFKBP51 in the liver were determined by quantitative RT-PCR. RESULTS: In the suprachiasmatic nucleus of control rats, rPer2 and rDBP mRNA expression levels showed robust circadian patterns with peak levels at ZT 06 and ZT 10, respectively. LPS significantly suppressed both genes on day 1 but recovery was noted on day 2. Similarly, LPS significantly suppressed rPer1, rPer2, rDBP, rPPARA, and rFKBP51 mRNA expression levels in the liver on day 1 but recovery was noted on day 2, whereas a robust circadian pattern was noted in the control group. CONCLUSION: Our results indicate that LPS causes transient suppression of the biological clock genes and suggest that the biological clock plays an important role in the response to systemic inflammatory stimulation.

Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (SPG4) located to 2p22-p21 is the most common form of autosomal dominant (AD) HSP. We performed PCR-based direct sequencing of SPG4, followed by a linkage analysis and subsequent Southern blot analysis in large Japanese kindred where 20 of 33 members were evaluated neurologically, and consequently 6 were affected with HSP. Clinical evaluation showed that the mean age at disease onset of the patients was older and the disability was less severe than those of previously reported typical patients with SPG4 mutations. Direct sequencing of genomic DNA and RT-PCR product did not show a SPG4 mutation despite of a strong linkage to the SPG4 locus at 2p. Southern blot analysis suggested a deletion involving the 5'-UTR of SPG4. Further sequence analysis confirmed a heterozygous 2307-bp deletion spanning from the 5'-UTR to intron 1 of SPG4. The results suggested that transcription of the mutated allele starts from an authentic initiation site, but lacks an authentic translational start site of exon 1 because of a deficient splice donor site and coding region. The abnormal transcripts may result in rapid RNA decay. The novel refractory mutation we identified widens the spectrum of SPG4 mutations. These findings suggest that structural genomic abnormalities of SPG4 are more frequent than expected, and this explains previously reported cases more feasibly in which SPG4 mutations were failed to be identified but the disease was linked to 2p.